Huntington's Disease (HD) is an hereditary degenerative disorder of grey matter characterized by abnormal movements and psychiatric symptoms and a degeneration of striatal cholinergic and GABAergic neurons with sparing of dopaminergic striatal afferents. During the period of support, we have demonstrated that intra-striatal injection of nanamole amounts of the neuroexcitant, kainic acid (KA), reproduces the neuropathologic and neurochemical alterations of HD in the rat nigro-striatal circuit. Preliminary evidence indicates that the mechanism of selective neurotoxicity of KA is complex and may involve the activation of highly specific receptors on vulnerable neurons; however, excitatory input to these neurons plays a permissive role in the neurotoxic action. In the proposed studies, we plan to characterize better the mechanism of neurotoxicity of kainic acid. 1) The receptor sites with which kainic acid interacts will be studied by means of ligand-binding techniques with regard to ontogenesis, phylogenetic distribution and interaction with amino acids and ions. 2) Receptor activation by KA at nerve terminals and on nerve cell bodies will be determined by measuring release of neurotransmitters from prelabeled brain slices incubated in vitro. 3) The mechanism whereby anesthetics antagonize th neurotoxicity of kainic acid will be examined by correlating the effects of these drugs on EEG and on KA-induced neuronal degeneration in the hippocampus. 4) The acute effects of KA on striatal energy metabolites, an early index of neuronal degeneration, will be determined; the reversibility of these metabolic effects will be defined by "cell rescue" with pentobarbital. 5) The mechanism involved in the acute release of norepinephrine following hippocampal injection of kainic acid will be explored by a combination of lesion studies in vivo and release studies in vitro. These studies will provide a basis for correlating KA's neurotoxicity with receptor activation and cooperative interaction with excitatory afferents and may shed light on a final common pathway involved in selective neuronal vulnerability in neurodegenerative disorders of grey matter such as HD.